Contact lenses, either hard or soft, especially those designed for extended wear, have been associated with bacterial infections of the eye, as bacteria and fungi can easily colonize the contact lens and grow between the contact lens and the cornea in an environment that provides adequate moisture, favorable temperature and suitable nutrients. Bacterial keratitis, commonly associated with contact lens wear, is a destructive disease of the cornea that is often caused by Pseudomonas aeruginosa. The creation of an antimicrobial contact lens that can prevent colonization and reduce the bacterial load, especially at the cornea/lens interface, could result in a reduction in the incidence of serious eye infections.
Hard contact lenses tend to mechanically damage the cornea. This allows microorganisms to invade and cause infection. Those for continuous wear, which have recently been increasing in popularity, are particularly dangerous. Further, bacteria, fungi, etc. may grow on the surface of both hard and soft contact lenses in a lens container and even the lens container itself, sometimes causing corneal infectious diseases.
Water-containing soft contact lenses, while comfortable to apply, are susceptible to colonization by bacteria and fungi, both on the surfaces and within the body of the soft contact lenses because of their own hydrophilic properties, as well as their high water content. This colonization of lenses with bacteria and/or fungi can cause serious infectious diseases. Moreover, these contact lenses demand care in handling and the sterilization treatments are tedious.
Contact lenses are worn on the cornea of the eye to improve sight. Both hard and soft contact lenses require periodic cleaning and disinfecting to remove protein deposits and undesirable microbes from their surfaces. In most cases, the lens is removed from the eye, cleaned with a lens cleaning solution and subsequently disinfected. After disinfection, the lens usually is rinsed with saline solution before placement in the eye.
Disinfecting treatments should effectively disinfect the lens without causing toxicity to the eye. Thousands of compositions exist which are capable of disinfecting, but which exhibit toxic or undesirable discomfort to the eye when applied to lenses. Lens users sometimes fail to rinse the disinfectant solution from their lenses before placing back into their eyes. In some cases, lens wearers rinse their lenses poorly. Sometimes, the disinfecting composition adheres to or adsorbs into the lens itself, such that even after a rinse, the relatively toxic substances from the disinfectant solution may still be temporarily retained within the surface of the lens. When that occurs, the toxic substances may be released into the eye once the lens is re-inserted. For these reasons, a desirable disinfectant solution preferably does not contain any compositions in concentration levels that exceed toxicity limits for the eye.
One of the problems connected with soft contact lenses is the method used for their sterilization and cleaning. The very property of hydrophilic soft lenses which allows them to absorb up to 150 percent water by weight also allows preservatives, which might otherwise be used for cleaning and sterilization, to be absorbed and even concentrated before later release when the soft contact lens is on the eye. The release may be much slower than the uptake, which allows the preservative to build up in the lenses. This buildup eventually affects the physical characteristics of the lenses including dimension, color, etc. Additionally, buildup of preservatives can damage or stain the contact lens itself and/or ultimately harm the sensitive tissues of the conjunctivae or cornea.
Contact lenses are commonly worn on a daily basis and kept in a storage case/solution during the night hours or whenever they are not being worn. During wear and normal handling, microorganisms, as well as biomolecules such as lipids, proteins, etc. can adhere to contact lenses and thus be transferred to the storage case/solution. Furthermore, a tear film containing proteins, lipids, and even microorganisms, and represents the natural flora of the ocular surface, covers the surface of the eye. Any of the components found in the tear film, on the external surface of the eye, or the surrounding skin can be carried into the storage case/solution on the contact lens.
Some of the microorganisms that may be transferred from the eye or fingers to the storage case/solution may multiply therein, and may later be pathogenic to the human cornea or other ocular structures. When the contact lens is returned to the eye following its overnight soaking period, it is possible for these pathogens to be transferred to the surface of the eye. Although human tears contain natural antimicrobial agents, a pathogen-bearing lens in contact with the cornea of the eye can serve as a reservoir for infection that might overcome the eye's natural defenses. This is especially true for soft contact lens as the material tends to absorb the microorganisms. The result of microbial growth—bacterial, protozoan or even fungal—can cause damage to the eye resulting in impaired vision and even blindness. Therefore, contact lenses should be disinfected daily to remove pathogenic organisms. This is usually done overnight (six to eight hours) in order to protect the wearer's eyes from infection.
The method for evaluating the effectiveness of a disinfectant generally involves determination the agent's ability to reduce the numbers of viable organisms within the normal contact lens storage time between wearings (six to eight hours, i.e., “overnight”). This reduction of organism numbers is typically reported in terms of the change in the common log of the microbial population following exposure to the antimicrobial agent. For example, if the agent within a challenge solution has effected a reduction in a particular organism from 106 colony forming units (cfu) per milliliter (ml) to 102 cfu/ml within six hours of exposure the change, or “log reduction”, would be reported as 4.0 (logs). In other words, the number of viable organisms has been reduced to one ten-thousandth of the original level.
These tests are most often performed by challenging the agent within solution with a concentrated viable inoculum (e.g., 105-106 cfu/ml) of each test organism. Samples are withdrawn at different timepoints, plated on growth agar and the number of viable organisms determined by colony counts. Of particular interest is the duration of typical overnight storage of soft contact lenses. It should be apparent that such a challenge represents a worst case scenario since a far greater number of microbes is added than would ever be expected on a contact lens. Further, it should also be apparent that the results of the test may be significantly influenced by other components of the solution besides the disinfectant agent.
In the case of contact lens and ophthalmic solutions, various agents are added to enhance compatibility with the eye. To avoid stinging or irritation it is important that the solution possess a tonicity and pH within the physiological range, e.g., 200-350 mOsmol/L for tonicity, and 6.5-8.5 for pH. To this end, various buffering and osmotic agents are often added. The simplest osmotic agent is sodium chloride since this is a major solute in human tears. In addition, propylene glycol, lactulose, trehalose, sorbitol, mannitol or other osmotic agents may also be added to replace some or all of the sodium chloride. Also, various buffer systems such as citrate, phosphate (appropriate mixtures of Na2 HPO4, NaH2PO4, and KH2PO4), borate (boric acid, sodium borate, potassium tetraborate, potassium metaborate and mixtures), bicarbonate, and tromethamine and other appropriate nitrogen-containing buffers (such as ACES, BES, BICINE, BIS-Tris, BIS-Tris Propane, HEPES, HEPPS, imidazole, MES, MOPS, PIPES, TAPS, TES, Tricine) can be used to ensure a physiologic pH between about pH 6.5 and 8.5. Under these circumstances, studies and development of contact lenses endowed with antimicrobial properties have been promoted.
Bacteria and fungi can also colonize contact lens-care articles, such as containers, to cause secondary infection. Therefore, it has been proposed that addition of an antimicrobial agent to the lens soaking solution, lens cleaner, or storage container may prevent microorganism growth.
Large quantities and/or high concentrations of antimicrobial agents can be toxic to the eye and the body. Hence, methods for controlling microorganisms that do not involve the addition of an antimicrobial agent have been studied. Resins coated with an antimicrobial substance have been proposed, but they are unsuitable for use with contact lens-care articles because they are extremely prone to leaching.
Where antimicrobial properties are imparted to a contact lens per se, special care for safety is required. This is because a contact lens comes into direct contact with the cornea and conjunctiva, and any substance eluted from the lens is carried by tears to the digestive tract. Accordingly, an antimicrobial substance that could be incorporated into contact lenses and/or related articles would be required to be highly active, heat stabile and to be firmly fixed to the lens so that it could not leach-out.
It should also be noted that the lens must exert the antimicrobial activity while retaining other properties essential to contact lenses, such as optical performance (i.e., transparency, uniformity, and heat stability), processability, strength, safety, and the like.
Contact lenses having inherently antimicrobial properties have been described. For instance, U.S. Pat. No. 5,515,117 (Dziabo) relates to contact lenses, and to contact lens cases having antimicrobial properties.
U.S. Pat. No. 5,520,910 (Hashimoto) describes that phosphonium salt type vinyl monomer graft-polymerized to the surface layer of a contact lens material imparts antimicrobial properties. In this case, a contact lens is subjected to a surface treatment, such as ultraviolet irradiation, corona discharge, or low-temperature plasma discharge, and the phosphonium salt type vinyl monomer is grafted to the radical so generated.
During wear, contact lenses are susceptible to the accumulation of proteinaceous materials that may adhere to the surface of the lens. Proteinaceous materials include, lysozyme, lactoferrin, albumin, and mucoproteins, and all constituents of lachrymal tears. Contact lenses that are repeatedly worn over an extended period of time must be cleaned to remove these materials as part of a routine care regimen.
If contact lenses are not properly cleaned, lysozyme, mucoproteins, and the like can accumulate on the lenses and may lead to the lens wearer experiencing discomfort or a loss of visual acuity. The presence of proteinaceous deposits may also decrease gas permeability and/or adversely affect the spectral characteristics of the lenses. Proteinaceous deposits may also block the efficacy of antimicrobials that are bound to the lens surface.
Fungal keratitis is a rare, but serious corneal infection that is sometimes associated with contact lens wear. In 2006, there was a sharp increase in the number of reported cases of Fusarium keratitis worldwide [Chang, D. C., et al, JAMA 296(8) p 953-963 (2006)].
In addition to contact lenses, other surfaces have been associated with colonization of bacteria, fungi, and other microbes. Examples of such surfaces include the surfaces of medical devices and health care equipment, food service items, general personal-use consumer goods, infant care items, kitchen and bathroom surfaces, as well as shared equipment. Bacteria, fungi, and other microbes can colonize on the surfaces especially when the surfaces are used in an environment that provides adequate moisture, favorable temperature, and suitable nutrients. If left untreated, surfaces can serve as a vehicle to transmit disease between individuals who may come in contact with the surfaces.
Disinfecting treatments are known in the art. However, many exhibit toxic or other undesirable characteristics that may preclude their use in a variety of circumstances. For example, bleach is an effective antimicrobial. But its use on some surfaces can have a negative impact on the surface itself. Residual bleach on the surface of a medical device, such as a syringe, can be toxic to individuals who use the syringe or may react with medicines drawn into the syringe. Similarly, residual bleach on infant care items, such as bottles or cribs, could negatively impact the health of an infant who comes in contact with the item.
Methods of binding quaternary ammonium polymers to surfaces are well known in the art. U.S. Patent Application Publication Nos. 2002/0177828 A1 and 2005/0033251 A1 as well as U.S. Pat. Nos. 7,045,673 B1, 7,151,139 and 6,146,688 and International Patent Application WO 2007/024974 A3 disclose various methods of binding quaternary ammonium polymers to impart antimicrobial activity to certain surfaces. These patents, patent applications and publications are incorporated by reference herein.
There are a variety of methods to bond quaternary ammonium polymers to surfaces. Cellulose, ceramic, metal, or polymeric materials with hydroxyl groups or available reactive carbons on their surfaces can be used as a substrate for the cerium (IV) and other initiator catalyzed grafting reactions. The extent of grafting will be dependent on the surface hydroxyl concentration and the concentration of susceptible carbon atoms. Even materials which do not normally contain sufficient surface hydroxyl groups may be used as substrates, as many methods are available for introducing surface hydroxyl groups. These methods generally include hydrolysis or oxidation effected by methods such as heat, plasma-discharge, e-beam, UV, or gamma irradiation, peroxides, acids, ozonolysis, or other methods. It should be noted that methods other than cerium initiated grafting may also be used in the practice of this invention.
In addition to cerium, azo compounds such as AIBN (2,2′-azobisisobutyronitrile) are commonly used as initiators for vinyl polymerizations, but are not generally thought of as catalysts for preparation of graft copolymers. We have found, however, that a water-soluble derivative of AIBN (2,2′-Azobis[N-(2-carboxyethyl)-2-methylpropionamidine]tetrahydrate, or VA-057, available from Wako Specialty Chemicals) was a suitable initiator for the graft polymerization of quaternary vinyl monomers onto cellulosic substrates such as paper or onto starch substrates. AIBN, which is one of the most commonly used polymerization initiators, is not soluble in water, and thus cannot be used directly in aqueous solutions. AIBN is soluble in alcohols, however, and thus can possibly be used as an initiator for the graft polymerization of quaternary monomers onto cellulose since the monomers are also soluble in alcohols. It is also likely that AIBN could be used in an emulsion system in order to achieve similar results. Other potentially useful Azo initiators include: (2,2′-Azobis[2-(5-methyl-2-imidazolin-2-yl)propane]dihydrochloride, or VA-041; 2,2′-Azobis (2-methyl-N-[1,1-bis(hydroxymethyl)-2-hydroxyethyl]propionamide, or VA-080; 2,2′-Azobis(2-methylpropionamide) dihydrochloride, or V-50; 2,2′-Azobis(N-cyclohexyl-2-methylpropionamide), or Vam-111; 1,1′-Azobis(cyclohexane-1-carbonitrile); and numerous other similar compounds). Organic peroxides such as benzoyl peroxide (BPO) are also widely used as polymerization initiators. Just as in the case of AlBN (above), BPO is not water soluble, but it can possibly be used in alcoholic solution in order to graft quaternary vinyl monomers onto cellulose. Other potentially useful peroxide initiators include: (dicumyl peroxide, t-butyl peroxide, methylethylketone peroxide, and a variety of other peroxides, peroxyketals, peroxydicarbonates, and hydroperoxides). These and numerous other potentially useful catalysts are available from a variety of suppliers such as Lucidol-Penwalt, and Akzo. Combinations of two or more of the initiators described above are also effective. These catalysts or initiators can also be used to form crosslinked cellulose-quaternary grafted materials.
Alternatively, the cationic polyelectrolytes may also be applied via non-catalyzed methods. For example, an antimicrobial polymer can be applied to a substrate as an aqueous solution followed by a drying step. It is also possible to utilize mixed solvents, such as water/alcohol mixtures, for initial application of the antimicrobial to the substrate using the described process, combined with a drying step. This will depend on the solubility of the antimicrobial in the mixed solvent systems. For instance, mixtures of alcohol and water may be used. It may also be possible to use completely non aqueous solvent systems; however, it is necessary that the antimicrobial be soluble in the chosen solvent system.
It is known in the art that quaternary ammonium polymers that are bound to surfaces can impart a certain degree of antimicrobial efficacy and biofilm-resistance to the surfaces. U.S. Patent Application Publication Nos. 2002/0177828 A1 and 2005/0033251 A1 and U.S. Pat. Nos. 7,151,139 and 6,146,688 disclose methods of binding quaternary ammonium polymers to impart antimicrobial activity to surfaces. Other examples of quaternary ammonium compounds used to impart antimicrobial efficacy are discussed below.
U.S. Pat. No. 4,675,347 (Mochizuki et al.) describes an antimicrobial latex composition comprising a cationic natural rubber latex and an inorganic or organic salt of a quaternary ammonium compound. Citrate is listed as one of the many examples of suitable salts. The cationic antimicrobial agent is incorporated in the latex and has a long “pot life”. The antimicrobial agent is released in a controlled manner at a constant rate. The composition may be used in gloves, tubes, finger sacs, catheters, sponges, mattresses, bath mats, rubber cloth, binders, fabrics, footwear soles, ice bags, etc.
U.S. Pat. No. 6,534,075 (Hei et al.) describes sanitized substrates having residual antimicrobial activity which contain compositions comprising a quaternary amine, an oxidant, a halide source, and pH buffers (including citrate). Compositions are effective on substrates such as those used in food transport lines, liquid filtration equipment, filtering agents, belt sprays, storage facilities, air circulation systems, aseptic packaging, refrigerators and coolers, cutting boards, sinks, beverage chillers, garments, animal quarters, microbes on eggs, animal skins, etc.
U.S. Pat. No. 6,702,983 (Hu et al.) describes a method for inhibiting the attachment of microorganisms to biomaterial surface, such as a contact lens, with a solution of a composition comprising a cationic polysaccharide polymer which may further comprise a quaternary ammonium and antimicrobial groups. The cationic biomaterial may be covalently bound to the surface of the biomaterial, but it is not critical. Control of the ionic strength of the solutions unexpectedly affects the performance of the cationic cellulose polymer. Many substances, including citrate can be used to control the pH of the solution.
U.S. Pat. No. 7,001,873 (McDonnell et al.) describes an alkaline cleaner for prion infected surfaces such as medical and surgical instruments, pharmaceutical and food preparation facilities, floors, work surfaces, equipment, cages, tanks, and fluid lines. The cleaner comprises an anti-redeposition agent such as a citrate salt and a cationic polymer such as polyDADMAC.
While the above-mentioned art describe the use of quaternary ammonium compounds for use as antimicrobial agents, none describes the use of such compound in conjunction with a citrate treatment to enhance the antimicrobial effectiveness of the resulting compositions. It is an aspect of the present invention that the antimicrobial and biofilm resistance effects of the combining quaternary ammonium and citrate is greater than the sum of the effect of the individual components.